New Way Of Treating The Flu

What happens if the next big influenza mutation proves resistant to the available anti-viral drugs? This question is presenting itself right now to scientists and health officials this week at the World Health Assembly in Geneva, Switzerland, as they continue to do battle with H1N1, the so-called swine flu, and prepare for the next iteration of the ever-changing flu virus.Promising new research announced by Rensselaer Polytechnic Institute could provide an entirely new tool to combat the flu. The discovery is a one-two punch against the illness that targets the illness on two fronts, going one critical step further than any currently available flu drug.

"We have been fortunate with H1N1 because it has been responding well to available drugs. But if the virus mutates substantially, the currently available drugs might be ineffective because they only target one portion of the virus," said Robert Linhardt, the Ann and John H. Broadbent Jr. '59 Senior Constellation Professor of Biocatalysis and Metabolic Engineering at Rensselaer. "By targeting both portions of the virus, the H and the N, we can interfere with both the initial attachment to the cell that is being infected and the release of the budding virus from the cell that has been affected."

The findings of the team, which have broad implications for future flu drugs, will be featured on the cover of the June edition of European Journal of Organic Chemistry.

The influenza A virus is classified based on the form of two of its outer proteins, hemagglutinin (H) and neuraminidase (N). Each classification – for example H5NI "bird flu" or H1N1 "swine flu" – represents a different mutation of hemagglutinin and neuraminidase or H and N.

Flu drugs currently on the market target only the neuraminidase proteins, and disrupt the ability of the virus to escape an infected cell and move elsewhere to infect other healthy cells. The new process developed by Linhardt is already showing strong binding potential to hemagglutinin, which binds to sialic acid on the surface of a healthy cell, allowing the virus to entire the cell.

"We are seeing promising preliminary results that the chemistry of this approach will be effective in blocking the hemagglutinin portion of the disease that is currently not targeted by any drug on the market," he said.

In addition, Linhardt and his team have shown their compound to be just as effective at targeting neuraminidase as the most popular drugs on the market, according to Linhardt.

The approach can also be modified to specifically target the neuraminidase or the hemagglutinin, or both, depending on the type of mutation that is present in the current version of the flu, according to Linhardt.

In the next steps of his research, Linhardt will look at how their compounds bind to hemagglutinin, and he will test the ability to block the virus first in cell cultures and then in infected animal models.

"It is still early in the process," he said. "We are several steps away from a new drug, but this technique is allowing us to move very quickly in creating and testing these compounds."

The technique that Linhardt used is the increasingly popular technique of "click chemistry." Linhardt is among the first researchers in the world to utilize the technique to create new anti-viral agents. The process allows chemists to join small units of a substance together quickly to create a new, full substance.

In this case, Linhardt used the technique to quickly build a new derivative of sialic acid. Because it is chemically very similar to the sialic acid found on the surface of a cell, the virus could mistake the compound as the real sialic acid and bind to it instead of the cell, eliminating the connections to hemagglutinin and neuraminidase that are required for initial infection and spread of the infection in the body. The currently available drugs are translation-state inhibitors whose chemical structure allows them to only effectively target the neuraminidase.

The research was funded by the National Institutes of Health. Linhardt was joined in the research by Michel Weïwer, Chi-Chang Chen, and Melissa Kemp of Rensselaer.

Environmental Exposure To Particulates May Damage DNA In As Few As Three Days

Exposure to particulate matter has been recognized as a contributing factor to lung cancer development for some time, but a new study indicates inhalation of certain particulates can actually cause some genes to become reprogrammed, affecting both the development and the outcome of cancers and other diseases.The research will be presented on May 17, at the 105th International Conference of the American Thoracic Society in San Diego.

"Recently, changes in gene programming due to a chemical transformation called methylation have been found in the blood and tissues of lung cancer patients," said investigator Andrea Baccarelli, M.D., Ph.D., assistant professor of applied biotechnology at the University of Milan. "We aimed at investigating whether exposure to particulate matter induced changes in DNA methylation in blood from healthy subjects who were exposed to high levels of particulate matter in a foundry facility."

Researchers enrolled 63 healthy subjects who worked in a foundry near Milan, Italy. Blood DNA samples were collected on the morning of the first day of the work week, and again after three days of work. Comparing these samples revealed that significant changes had occurred in four genes associated with tumor suppression.

"The changes were detectable after only three days of exposure to particulate matter, indicating that environmental factors need little time to cause gene reprogramming which is potentially associated with disease outcomes," Dr. Baccarelli said.

"As several of the effects of particulate matter in foundries are similar to those found after exposure to ambient air pollution, our results open new hypotheses about how air pollutants modify human health," he added. "The changes in DNA methylation we observed are reversible and some of them are currently being used as targets of cancer drugs."

Dr. Baccarelli said the study results indicate that early interventions might be designed which would reverse gene programming to normal levels, reducing the health risks of exposure.

"We need to evaluate how the changes in gene reprogramming we observed are related to cancer risk," he said. "Down the road, it will be particularly important not only to show that these changes are associated with increased risk of cancer or other environmentally-induced diseases, but that, if we were able to prevent or revert them, these risks could be eliminated."

Session # A45: "Genetic Basis for Environmental and Occupational Respiratory Diseases." Abstract # 2589: "Effects of Particulate Matter Exposure on p16, p53, APC and RASSF1A Promoter Methylation" Poster Board # C51

Gene Key To Alzheimer's-like Reversal Identified: Success In Restoring Memories In Mice Could Lead To Human Treatments

A team led by researchers at MIT's Picower Institute for Learning and Memory has now pinpointed the exact gene responsible for a 2007 breakthrough in which mice with symptoms of Alzheimer's disease regained long-term memories and the ability to learn.In the latest development, reported in the May 7 issue of Nature, Li-Huei Tsai, Picower Professor of Neuroscience, and colleagues found that drugs that work on the gene HDAC2 reverse the effects of Alzheimer's and boost cognitive function in mice.

"This gene and its protein are promising targets for treating memory impairment," Tsai said. "HDAC2 regulates the expression of a plethora of genes implicated in plasticity — the brain's ability to change in response to experience — and memory formation.

"It brings about long-lasting changes in how other genes are expressed, which is probably necessary to increase numbers of synapses and restructure neural circuits, thereby enhancing memory," she said.

The researchers treated mice with Alzheimer's-like symptoms using histone deacetylase (HDAC) inhibitors. HDACs are a family of 11 enzymes that seem to act as master regulators of gene expression. Drugs that inhibit HDACs are in experimental stages and are not available by prescription for use for Alzheimer's.

"Harnessing the therapeutic potential of HDAC inhibitors requires knowledge of the specific HDAC family member or members linked to cognitive enhancement," Tsai said. "We have now identified HDAC2 as the most likely target of the HDAC inhibitors that facilitate synaptic plasticity and memory formation.

"This will help elucidate the mechanisms by which chromatin remodeling regulates memory," she said. It also will shed light on the role of epigenetic regulation, through which gene expression is indirectly influenced, in physiological and pathological conditions in the central nervous system.

"Furthermore, this finding will lead to the development of more selective HDAC inhibitors for memory enhancement," she said. "This is exciting because more potent and safe drugs can be developed to treat Alzheimer's and other cognition diseases by targeting this HDAC specifically," said Tsai, who is also a Howard Hughes Medical Institute investigator. Several HDAC inhibitors are currently in clinical trials as novel anticancer agents and may enter the pipeline for other diseases in the coming two to four years. Researchers have had promising results with HDAC inhibitors in mouse models of Huntington's disease.

Remodeling structures

Proteins called histones act as spools around which DNA winds, forming a structure in the cell nucleus known as chromatin. Histones are modified in various ways, including through a process called acetylation, which in turn modifies chromatin shape and structure. (Inhibiting deacetylation with HDAC inhibitors leads to increased acetylation.)

Certain HDAC inhibitors open up chromatin. This allows transcription and expression of genes in what had been a too tightly packaged chromatin structure in which certain genes do not get transcribed.

There has been exponential growth in HDAC research over the past decade. HDAC inhibitors are currently being tested in preclinical studies to treat Huntington's disease. Some HDAC inhibitors are on the market to treat certain forms of cancer. They may help chemotherapy drugs better reach their targets by opening up chromatin and exposing DNA. "To our knowledge, HDAC inhibitors have not been used to treat Alzheimer's disease or dementia," Tsai said. "But now that we know that inhibiting HDAC2 has the potential to boost synaptic plasticity, synapse formation and memory formation, in the next step, we will develop new HDAC2-selective inhibitors and test their function for human diseases associated with memory impairment to treat neurodegenerative diseases."

The researchers conducted learning and memory tasks using transgenic mice that were induced to lose a significant number of brain cells. Following Alzheimer's-like brain atrophy, the mice acted as though they did not remember tasks they had previously learned.

But after taking HDAC inhibitors, the mice regained their long-term memories and ability to learn new tasks. In addition, mice genetically engineered to produce no HDAC2 at all exhibited enhanced memory formation.

The fact that long-term memories can be recovered by elevated histone acetylation supports the idea that apparent memory "loss" is really a reflection of inaccessible memories, Tsai said. "These findings are in line with a phenomenon known as 'fluctuating memories,' in which demented patients experience temporary periods of apparent clarity," she said.

In addition to Tsai, co-authors are Picower postdoctoral associate Ji-Song Guan; and colleagues from Massachusetts General Hospital; Harvard Medical School; the Whitehead Institute for Biomedical Research; MIT's Department of Biology; the Dana Farber Cancer Institute; and the Netherlands Cancer Institute.

This work is supported by the National Institute for Neurological Disorders and Stroke, the Stanley Center for Psychiatric research at the Broad Institute of Harvard and MIT; the NARSAD, a mental health foundation, the National Cancer Institute, the Damon-Runyon Cancer Research Foundation; the Dutch Cancer Society; the National Institutes of Health; and the Robert A. and Renee E. Belfer Institute for Applied Cancer Science.